Inhibitors for GlyT-1

ABSTRACT

The present invention relates to compounds of formula I 
                         
wherein
     R 1 , R 2 ,   R 3 ,   R 4 , and   X are as defined herein or to pharmaceutically acceptable acid addition salts thereof, with the exception of   4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide,   4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,   4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-benzamide,   4-methyl-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide,   N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,   4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,   4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide and   N-[2-[(2,4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide. The compounds are useful in the treatment of neurological and neuropsychiatric disorders.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06119758.8, filed Aug. 30, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Schizophrenia is a progressive and devastating neurological diseasecharacterized by episodic positive symptoms such as delusions,hallucinations, thought disorders and psychosis and persistent negativesymptoms such as flattened affect, impaired attention and socialwithdrawal, and cognitive impairments (Lewis D A and Lieberman J A,Neuron, 2000, 28:325-33). For decades research has focused on the“dopaminergic hyperactivity” hypothesis which has led to therapeuticinterventions involving blockade of the dopaminergic system (VandenbergR J and Aubrey K R., Exp. Opin. Ther. Targets, 2001, 5 (4): 507-518;Nakazato A and Okuyama S, et al., 2000, Exp. Opin. Ther. Patents, 10(1): 75-98). This pharmacological approach poorly address negative andcognitive symptoms which are the best predictors of functional outcome(Sharma T., Br. J. Psychiatry, 1999, 174 (suppl. 28): 44-51).

A complementary model of schizophrenia was proposed in the mid-1960'based upon the psychotomimetic action caused by the blockade of theglutamate system by compounds like phencyclidine (PCP) and relatedagents (ketamine) which are non-competitive NMDA receptor antagonists.Interestingly in healthy volunteers, PCP-induced psychotomimetic actionincorporates positive and negative symptoms as well as cognitivedysfunction, thus closely resembling schizophrenia in patients (Javitt DC et al., 1999, Biol. Psychiatry, 45: 668-679 and refs. herein).Furthermore transgenic mice expressing reduced levels of the NMDAR1subunit displays behavioral abnormalities similar to those observed inpharmacologically induced models of schizophrenia, supporting a model inwhich reduced NMDA receptor activity results in schizophrenia-likebehavior (Mohn A R et al., 1999, Cell, 98: 427-236).

Glutamate neurotransmission, in particular NMDA receptor activity, playsa critical role in synaptic plasticity, learning and memory, such as theNMDA receptors appears to serve as a graded switch for gating thethreshold of synaptic plasticity and memory formation (Hebb DO, 1949,The organization of behavior, Wiley, N.Y.; Bliss T V and CollingridgeGL, 1993, Nature, 361: 31-39). Transgenic mice overexpressing the NMDANR2B subunit exhibit enhanced synaptic plasticity and superior abilityin learning and memory (Tang J P et al., 1999, Nature: 401-63-69).

Thus, if a glutamate deficit is implicate in the pathophysiology ofschizophrenia, enhancing glutamate transmission, in particular via NMDAreceptor activation, would be predicted to produce both anti-psychoticand cognitive enhancing effects.

The amino acid glycine is known to have at least two important functionsin the CNS. It acts as an inhibitory amino acid, binding to strychninesensitive glycine receptors, and it also influences excitatory activity,acting as an essential co-agonist with glutamate forN-methyl-D-aspartate (NMDA) receptor function. While glutamate isreleased in an activity-dependent manner from synaptic terminals,glycine is apparently present at a more constant level and seems tomodulate/control the receptor for its response to glutamate.

One of the most effective ways to control synaptic concentrations ofneurotransmitter is to influence their re-uptake at the synapses.Neurotransmitter transporters by removing neurotransmitters from theextracellular space, can control their extracellular lifetime andthereby modulate the magnitude of the synaptic transmission (GainetdinovR R et al, 2002, Trends in Pharm. Sci., 23 (8): 367-373).

Glycine transporters, which form part of the sodium and chloride familyof neurotransmitter transporters, play an important role in thetermination of post-synaptic glycinergic actions and maintenance of lowextracellular glycine concentration by re-uptake of glycine intopresynaptic nerve terminals and surrounding fine glial processes.

Two distinct glycine transporter genes have been cloned (GlyT-1 andGlyT-2) from mammalian brain, which give rise to two transporters with˜50% amino acid sequence homology. GlyT-1 presents four isoforms arisingfrom alternative splicing and alternative promoter usage (1a, 1b, 1c and1d). Only two of these isoforms have been found in rodent brain (GlyT-1aand GlyT-1b). GlyT-2 also presents some degree of heterogeneity. TwoGlyT-2 isoforms (2a and 2b) have been identified in rodent brains.GlyT-1 is known to be located in CNS and in peripheral tissues, whereasGlyT-2 is specific to the CNS. GlyT-1 has a predominantly glialdistribution and is found not only in areas corresponding to strychninesensitive glycine receptors but also outside these areas, where it hasbeen postulated to be involved in modulation of NMDA receptor function(Lopez-Corcuera B et al., 2001, Mol. Mem. Biol., 18: 13-20). Thus, onestrategy to enhance NMDA receptor activity is to elevate the glycineconcentration in the local microenvironment of synaptic NMDA receptorsby inhibition of GlyT-1 transporter (Bergereon R. Et al., 1998, Proc.Natl. Acad. Sci. USA, 95: 15730-15734; Chen L et al., 2003, J.Neurophysiol., 89 (2): 691-703).

Glycine transporters inhibitors are suitable for the treatment ofneurological and neuropsychiatric disorders. The majority of diseasesstates implicated are psychoses, schizophrenia (Armer R E and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mooddisorders such as severe major depressive disorder, mood disordersassociated with psychotic disorders such as acute mania or depressionassociated with bipolar disorders and mood disorders associated withschizophrenia, (Pralong E T et al., 2002, Prog. Neurobiol., 67:173-202), autistic disorders (Carlsson M L, 1998, J. Neural Transm. 105:525-535), cognitive disorders such as dementias, including age relateddementia and senile dementia of the Alzheimer type, memory disorders ina mammal, including a human, attention deficit disorders and pain (ArmerR E and Miller D J, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572).

Thus, increasing activation of NMDA receptors via GlyT-1 inhibition maylead to agents that treat psychosis, schizophrenia, dementia and otherdiseases in which cognitive processes are impaired, such as attentiondeficit disorders or Alzheimer's disease.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

wherein

-   R¹ is lower alkyl, aryl or heteroaryl, wherein aryl and heteroaryl    are optionally substituted by halogen, lower alkyl, lower alkoxy,    lower alkyl substituted by halogen, lower alkoxy substituted by    halogen, cyano, amino, di-lower alkyl amino or morpholinyl;-   R² is lower alkyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl or    —(CH₂)_(n)-cycloalkyl, wherein the aryl or heteroaryl groups are    optionally substituted by one or more substituents selected from the    group consisting of halogen, lower alkyl, cyano, or lower alkoxy;-   R³ is hydrogen or lower alkyl;-   R⁴ is aryl or heteroaryl, wherein aryl and heteroaryl are optionally    substituted by one or more substituents selected from the group    consisting of halogen, lower alkyl substituted by halogen, lower    alkoxy substituted by halogen, lower alkyl;-   X is a bond or —OCH₂—;-   n is 0, 1 or 2;    or pharmaceutically acceptable acid addition salts thereof, with the    exception of-   4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide,-   4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,-   4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-phenylmethyl-benzamide,-   4-methyl-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-phenylmethyl-benzamide,-   N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,-   4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,-   4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-phenylmethyl-benzamide    and-   N-[2-[(2,    4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide.

The first excepted compound has been described in Journal of theChemical Society, Perkin Transactions 1: Organic and Bio-OrganicChemistry (1972), (7), 909-13 in a cyclisation process ofα-acylamino-acids. The other excepted compounds have been listed in theCAS registry file.

Furthermore, the invention includes all racemic mixtures, all theircorresponding enantiomers and/or optical isomers.

The present invention also provides pharmaceutical compositionscontaining a compound of formula I or a pharmaceutical salt thereof. Theinvention also provides methods for the preparation of the compounds andcompositions of the invention.

Compounds of general formula I are good inhibitors of the glycinetransporter 1 (GlyT-1) and have a good selectivity to glycinetransporter 2 (GlyT-2) inhibitors. The invention provides methods forthe treatment of diseases related to activation of NMDA receptors viaGlyT-1 inhibition, such as psychoses, dysfunction in memory andlearning, schizophrenia, dementia and other diseases in which cognitiveprocesses are impaired, such as attention deficit disorders orAlzheimer's disease. The preferred indications of the present inventionare schizophrenia, cognitive impairment and Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

As used herein, the term “lower alkyl” denotes a saturated straight- orbranched-chain hydrocarbon group containing from 1 to 7 carbon atoms,for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl,2-butyl, t-butyl and the like. Preferred alkyl groups are groups with1-4 carbon atoms.

The term “cycloalkyl” denotes a saturated or partially saturatedcarbocyclic ring containing from 3 to 7 carbon atoms, for examplecyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl or cycloheptenyl.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “aryl” denotes a monovalent cyclic aromatic hydrocarbon radicalhaving 6 to 12 ring atoms and consisting of one or more fused rings inwhich at least one ring is aromatic in nature, for example phenyl ornaphthyl.

The term “heteroaryl” denotes a cyclic aromatic hydrocarbon radical,containing one, two or three heteroatoms selected from the groupconsisting of oxygen, sulphur or nitrogen wherein at least one ring isaromatic in nature, for example pyridyl, quinoxalinyl,dihydrobenzofuranyl, thiophenyl, benzothiophenyl, isoxazolyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl and isothiazolyl.

The term “lower alkyl substituted by halogen” denotes a lower alkylgroup as defined above, wherein at least one hydrogen atom is replacedby a halogen atom, for example the following groups: CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CHF₂, CH₂CH₂F, CH₂CH₂CF₃, CH₂CH₂CH₂CF₃, CH₂CH₂Cl, CH₂CF₂CF₃,CH₂CF₂CHF₂, CF₂CHFCF₃, C(CH₃)₂CF₃, CH(CH₃)CF₃ or CH(CH₂F)CH₂F.

The term “lower alkoxy” denotes a alkyl group wherein the lower alkylresidue is as defined above and which is attached via an oxygen atom.

The term “lower alkoxy substituted by halogen” denotes an alkoxy group,wherein at least one hydrogen atom is replaced by halogen as definedabove.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The present invention provides compounds of formula I

wherein

-   R¹ is lower alkyl, aryl or heteroaryl, wherein aryl and heteroaryl    are optionally substituted by halogen, lower alkyl, lower alkoxy,    lower alkyl substituted by halogen, lower alkoxy substituted by    halogen, cyano, amino, di-lower alkyl amino or morpholinyl;-   R² is lower alkyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl or    —(CH₂)_(n)-cycloalkyl, wherein the aryl or heteroaryl groups are    optionally substituted by one or more substituents selected from the    group consisting of halogen, lower alkyl, cyano, or lower alkoxy;-   R³ is hydrogen or lower alkyl;-   R⁴ is aryl or heteroaryl, wherein aryl and heteroaryl are optionally    substituted by one or more substituents selected from the group    consisting of halogen, lower alkyl substituted by halogen, lower    alkoxy substituted by halogen, lower alkyl;-   X is a bond or —OCH₂—;-   n is 0, 1 or 2;    or pharmaceutically acceptable acid addition salts thereof, with the    exception of-   4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide,-   4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,-   4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-benzamide,-   4-methyl-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide,-   N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,-   4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,-   4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide    and-   N-[2-[(2,4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide.

Preferred compounds of formula I are those, wherein X is a bond.

Preferred compounds of formula I of the present invention are furtherthose, wherein R¹ and R⁴ are both monosubstituted aryl, preferablyhalogen substituted phenyl, for example the following compounds:

-   4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide,-   4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,3-difluoro-benzyl)-benzamide,-   4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)-benzamide,-   4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-thiophen-2-ylmethyl-benzamide,-   4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-methoxy-benzyl)-benzamide,-   4-Chloro-N-(3-chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-benzamide    and-   4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-benzamide.

Further preferred compounds are those, wherein R¹ and R⁴ are bothmonosubstituted aryl, for R¹ preferably methoxy substituted phenyl andfor R⁴ preferably halogen substituted phenyl, for example the followingcompounds:

-   N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-4-methoxy-benzamide    and-   N-(3-Chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-4-methoxy-benzamide.

Preferred compounds of formula I of the present invention are furtherthose, wherein R¹ is heteroaryl, preferably benzothiophenyl, for examplethe following compounds:

-   Benzo[b]thiophene-2-carboxylic acid    (2-chloro-benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-amide,-   Benzo[b]thiophene-2-carboxylic acid    (2-chloro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,-   Benzo[b]thiophene-2-carboxylic acid    (3,5-difluoro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,-   Benzo[b]thiophene-2-carboxylic acid    [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,6-difluoro-benzyl)-amide,-   Benzo[b]thiophene-2-carboxylic acid    [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,3-difluoro-benzyl)-amide    and-   Benzo[b]thiophene-2-carboxylic acid    [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(3,5-difluoro-benzyl)-amide.

Preferred compounds of formula I of the present invention are furtherthose, wherein R¹ and R⁴ are monosubstituted aryl, preferably halogensubstituted phenyl for R¹ and CF₃ substituted phenyl for R⁴, for examplethe following compound:

-   N-(2-Chloro-benzyl)-4-fluoro-N-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-benzamide.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocesses described below, which processes comprise

a) reacting a compound of formula

with a compound of formulaR²—NH₂  IIand with a compound of formula

in the presence of N-ethyldiisopropylamineto produce a compound of formula

wherein the substituents are as defined above, or

b) reacting a compound of formula

with a compound of formula

in presence of triethylamineto produce a compound of formula

wherein the substituents are as defined above or

c) reacting a compound of formulaNHR³R⁴  IXwith a compound of formula

in the presence of N-ethyldiisopropylamine and HATU[O-(7-Azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluroniumhexafluorophosphate],to produce a compound of formula

wherein the substituents are as defined above, or

d) reacting a compound of formula

with a compound of formula

in the presence of triethylamine,to produce a compound of formula

wherein the substituents are as defined aboveand

if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts.

The acid addition salts of the basic compounds of formula I can beconverted to the corresponding free bases by treatment with at least astoichiometric equivalent of a suitable base such as sodium or potassiumhydroxide, potassium carbonate, sodium bicarbonate, ammonia, and thelike.

The compounds of formula I can be prepared in accordance with processvariant a) to d), with the following schemes and with working examples1-128.

The starting material is commercially available or can be prepared inaccordance with known methods.

Procedure A

This procedure is used to prepare Example 34(N-phenyl-N-(p-tolylcarbamoyl-methyl)-6-trifluoromethyl-nicotinamide).

To a compound of formula III, for example2-bromo-N-(4-methyl-phenyl)-acetamide, in THF is added a compound offormula II, for example aniline and N-ethyldiisopropylamine, and acompound of formula IV, for example 6-trifluoromethyl-nicotynoylchloride, and the reaction mixture is stirred over night at reflux. Thenthe reaction is concentrated in vacuo, and the reaction mixture ispurified in conventional manner.

Procedure B

This procedure is used to prepare Example 30:N-[(3,4-dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethylbenzamide.

Step 1: Compound of Formula V

To a compound of formula III, for example2-bromo-N-(3,4-dichloro-phenyl)-acetamide, in THF is added a compound offormula II, for example aniline and N-ethyldiisopropylamine, and thereaction mixture is stirred over night at reflux. The precipitated saltis then filtered off, and the filtrate was then concentrated in vacuo.The residue was then purified in conventional manner.

Step 2: Compound of Formula I

To a compound of formula V, for exampleN-(3,4-dichloro-phenyl)-2-phenylamino-acetamide, in THF is addedtriethylamine and a compound of formula IV, for example3-trifluoromethylbenzoyl chloride, and the reaction mixture is stirredat room temperature for about 30 minutes. Water is then added to themixture until precipitation occurred, and the mixture is stirred for 5minutes. Then the precipitate is isolated by filtration and washed.

Procedure C

This procedure is used to prepare Example 30:4-chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamide.

Step 1: Compound of Formula VII

To a compound of formula VI, for example(2,6-dichloro-benzylamino)-acetic acid ethyl ester, in suspension THF isadded triethylamine and a compound of formula IV, for example4-methoxybenzoyl chloride, and the reaction mixture is stirred at roomtemperature for 10 min. Water is then added to the reaction mixture, andthe aqueous phase is extracted with diethylacetate. The combined organicphases are then dried, concentrated in vacuo and purified.

Step 2: Compound of Formula VIII

To a compound of formula VII, for exampleN-(3,4-dichloro-phenyl)-2-phenylamino-acetamide, in ethanol is addedNaOH, and the reaction mixture is stirred at room temperature for about3 hours. The reaction mixture is then neutralized by addition of HCl,and the ethanol is eliminated by evaporation. Water and ethyl acetate isthen added to the residue. The organic phase is separated, and theaqueous phase is extracted with ethylacetate. The combined organic phaseis then washed again with water, dried and concentrated in vacuo.

Step 3: Compound of Formula I

To a solution of a compound of formula IX, for example 3-chloroaniline,in DMF is added N-ethyldiiopropylamine, a compound of formula VIII, forexample [(2,6-dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid,and HATU; and the reaction mixture is stirred at room temperature overnight. Then water is added until precipitation occurs, and theprecipitate is isolated by filtration and washed with a mixture of waterand ethanol to yield the title compound.

Procedure D

This procedure was used to prepare Example 1:4-chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide.

To a compound of formula III-1, for exampleN-1-(3-chlorophenyl)-2-chloroacetamide, in DMF is added a compound offormula II, for example 2,6-difluorobenzylamine and triethylamine, and acompound of formula IV, such as 4-chlorobenzoyl chloride. The reactionmixture is stirred at room temperature for about 15 min and thenpurified.

Procedure E

This procedure was used to prepare Example 97:N-[(3,4-dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamide.

Step 1: Hydrobromide of a Compound of Formula V-1

To a solution of a compound of formula III, for example2-bromo-N-(3,4-dichloro-phenyl)-acetamide, in dichloromethane at 0° C.is slowly added isobutylamine in dichloromethane. The reaction mixtureis allowed to warm up to room temperature and then stirred for another24 hours. Then the salt is filtered off and the filtrate is concentratedin vacuo. The residue is then purified.

Step 2: Compound of Formula I-1.

To a solution of a compound of formula V-1, such asN-(3,4-dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide, in THFare slowly added a solution of triethylamine in THF and a solution of acompound of formula IV, for example 4-methoxybenzoyl chloride, in THF,and the reaction mixture is stirred at room temperature for about 24hours. Then water is added to the reaction mixture, and the precipitateis isolated by filtration and then purified.

The compounds of formula I and their pharmaceutically usable additionsalts possess valuable pharmacological properties. Specifically, thecompounds of the present invention are good inhibitors of the glycinetransporter I (GlyT-1).

The compounds were investigated in accordance with the test givenhereinafter.

Solutions and Materials

DMEM complete medium: Nutrient mixture F-12 (Gibco Life-technologies),fetal bovine serum (FBS) 5%, (Gibco life technologies),Penicillin/Streptomycin 1% (Gibco life technologies), Hygromycin 0.6mg/ml (Gibco life technologies), Glutamine 1 mM Gibco life technologies)

Uptake buffer (UB): 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl₂,2.5 mM KCl, 2.5 mM MgSO₄, 10 mM (+) D-glucose.

Flp-in™-CHO (Invitrogen Cat n° R758-07) cells stably transfected withmGlyT1b cDNA.

Glycine Uptake Inhibition Assay (mGlyT-1b)

On day 1 mammalian cells, (Flp-in™-CHO), transfected with mGlyT-1b cDNA,were plated at the density of 40,000 cells/well in complete F-12 medium,without hygromycin in 96-well culture plates. On day 2, the medium wasaspirated and the cells were washed twice with uptake buffer (UB). Thecells were then incubated for 20 min at 22° C. with either (i) nopotential competitor, (ii) 10 mM non-radioactive glycine, (iii) aconcentration of a potential inhibitor. A range of concentrations of thepotential inhibitor was used to generate data for calculating theconcentration of inhibitor resulting in 50% of the effect (e.g. IC₅₀,the concentration of the competitor inhibiting glycine uptake of 50%). Asolution was then immediately added containing [³H]-glycine 60 nM (11-16Ci/mmol) and 25 μM non-radioactive glycine. The plates were incubatedwith gentle shaking and the reaction was stopped by aspiration of themixture and washing (three times) with ice-cold UB. The cells were lysedwith scintillation liquid, shaken 3 hours and the radioactivity in thecells was counted using a scintillation counter.

The compounds described in examples 1-128 have an IC₅₀ data <1.0 μM. TheIC₅₀ data (<0.4 μM) for representative compounds 1-128 is be provided intable 2.

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example compounds of formulaI and their pharmaceutically suitable acid addition salts, and apharmaceutically acceptable carrier. Such pharmaceutical compositionscan be in the form of tablets, coated tablets, dragées, hard and softgelatin capsules, solutions, emulsions or suspensions. Thepharmaceutical compositions also can be in the form of suppositories orinjectable solutions.

The pharmaceutical compounds of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic and organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active substance no carriers are however usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, glycerol,vegetable oil and the like. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

The pharmaceutical compositions can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The invention also provides a method for preparing compositions of theinvention which comprises bringing one or more compounds of formula Iand/or pharmaceutically acceptable acid addition salts and, if desired,one or more other therapeutically valuable substances into a galenicaladministration form together with one or more therapeutically inertcarriers.

The most preferred indications in accordance with the present inventionare those, which include disorders of the central nervous system, forexample the treatment or prevention of schizophrenia, cognitiveimpairment and Alzheimer's disease. The invention provides a method forthe treatment of schizophrenia, which comprises administering to anindividual a therapeutically effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof. The invention alsoprovides a method for the treatment of Alzheimer's disease, whichcomprises administering to an individual a therapeutically effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof. The invention further comprises a method for improvingcognition, which comprises administering to an individual atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, have to be adjusted to theindividual requirements in each particular case. In the case of oraladministration the dosage for adults can vary from about 0.01 mg toabout 1000 mg per day of a compound of general formula I or of thecorresponding amount of a pharmaceutically acceptable salt thereof. Thedaily dosage can be administered as single dose or in divided doses and,in addition, the upper limit can also be exceeded when this is found tobe indicated.

Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 5 mg 25mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. LactoseAnhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. MicrocrystallineCellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167831 Manufacturing Procedure 1. Mix items 1, 2, 3 and 4 and granulatewith purified water. 2. Dry the granules at 50° C. 3. Pass the granulesthrough suitable milling equipment. 4. Add item 5 and mix for threeminutes; compress on a suitable press. Capsule Formulation mg/capsuleItem Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70 4.Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into asuitable capsule.

The following examples illustrate the present invention without limitingit. All temperatures are given in degree Celsius.

Procedure A

This procedure is used to prepare Example 34

N-Phenyl-N-(p-tolylcarbamoyl-methyl)-6-trifluoromethyl-nicotinamide

To 2-bromo-N-(4-methyl-phenyl)-acetamide (100 mg) in THF (3.0 mL) wasadded aniline (41 mg) and N-ethyldiisopropylamine and6-trifluoromethyl-nicotynoyl chloride (110 mg) the reaction mixture wasstirred over night at reflux. Then the reaction was concentrated invacuo and the reaction mixture was purified by column chromatography toyield the title compound as a light brown solid (127 mg, 70%).Procedure B

This procedure was used to prepare Example 30

N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethylbenzamide Step 1: N-(3,4-Dichloro-phenyl)-2-phenylamino-acetamide

To 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (2 g) in THF (80 mL) wasadded aniline (41 mg) and N-ethyldiisopropylamine and the reactionmixture was stirred over night at reflux. The precipitated salt was thenfiltered off and the filtrate was then concentrated in vacuo. Theresidue was then purified by column chromatography to give the titlecompound as a light brown solid (1.3 g, mp=110-112° C.).

Step 2:N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethylbenzamide

To N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide (73 mg) in THF (3.1mL) was added tiethylamine (52 μL) and 3-trifluoromethylbenzoyl chloride(62 mg) and the reaction mixture was stirred at room temperature for 30minutes. To the mixture was then added water under precipitationoccurred and the mixture was stirred for 5 minutes. Then the precipitatewas isolated by filtration and washed with a mixture water-ethanol (1:1)to yield the title compound as a white solid (64 mg, mp=130-132° C.).

Procedure C

This procedure was used to prepare Example 30

4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamideStep 1: N-(3,4-Dichloro-phenyl)-2-phenylamino-acetamide

To (2,6-dichloro-benzylamino)-acetic acid ethyl ester (100 mg) insuspension THF (5 mL) was added triethylamine (0.08 mL) and4-methoxybenzoyl chloride (78 mg) and the reaction mixture was stirredat room temperature for 10 min. After such time the water was added tothe reaction mixture and the aqueous phase was extracted withdiethylacetate. The combined organic phases were then dried over sodiumsulfate, concentrated vacuo and purified by column chromatography toyield the title (128 mg). MS (m/e): 396.3 (M+H⁺)

Step 2: [(2,6-Dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid

To N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide in ethanol (10 mL)was added 1N NaOH (0.38 μL) and the reaction mixture was stirred at roomtemperature for 3 hours. After such time the reaction mixture wasneutralized by addition of 3N HCl and the ethanol was eliminated byevaporation. To the residue was added more water and ethyl acetate. Theorganic phase was separated and the aqueous phase was extracted withethylacetate. The combined organic phase was then washed again withwater, dried over sodium sulfate and concentrated in vacuo to yield thetitle compound (90 mg). MS (m/e): 366.0 (M−H).

Step 3:4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamide

To a solution of 3-chloroaniline (20 mg) in DMF (1.5 mL) was addedN-ethyldiiopropylamine (137 μL),[(2,6-Dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid (58 mg)and HATU (Across 365312) and the reaction mixture was stirred at roomtemperature over night. Then water was added until the precipitationoccurs and the precipitate was isolated by filtration and washed with amixture of water and ethanol (2:1) to yield the title compound (35 mg).MS (m/e): 479.2 (M+H⁺).

Procedure D

This procedure was used to prepare Example 1

4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide

To N1-(3-chlorophenyl)-2-chloroacetamide (61 mg) in DMF (1 mL) was added2,6-difluorobenzylamine (38 mg) and triethylamine (0.1 mL) and4-chlorobenzoyl chloride (58 mg) the reaction mixture was stirred atroom temperature for 15 min and then purified by HPLC preparative toyield the title compound (55 mg). MS (m/e): 447.0 (M−H).Procedure E

This procedure was used to prepare Example 97

N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamideStep 1: N-(3,4-Dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide

To a solution of 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (0.1 g) indichloromethane (80 mL) at 0° C. was slowly added of isobutylamine (52mg) in dichloromethane. The reaction mixture was allowed to warm up toroom temperature and then stirred for another 24 hours. Then the saltwas filtered off and the filtrate was concentrated in vacuo. The residuewas then purified by column chromatography to yield the title compoundas a white solid (0.1 g). MS (m/e): 357.1 (M+H⁺).

Step 2:N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamide

To a solution of N-(3,4-dichloro-phenyl)-2-isobutylamino-acetamidehydrobromide (0.090 g) in THF were slowly added a solution oftriethylamine (0.064 mg) in THF (5 mL) and a solution of4-methoxybenzoyl chloride (47 mg) in THF (5 mL) and the reaction mixturewas stirred at room temperature for 24 hours. Then water was added tothe reaction mixture and the precipitate was isolated by filtration andthen purified by column chromatography to yield the title compound (78mg). MS (m/e): 409.2 (M−H, 100%).

The following starting materials for preparation of compounds of formulaI have been used:

TABLE 1 Amine/ Chloro amide or Exp Procedure Aniline bromo amide Acylchloride 1 D 2,6- N1-(3-Chlorophenyl)- 4-ChlorobenzoylDifluorobenzylamine 2-chloroacetamide chloride 2 D 3,4-N1-(3-Chlorophenyl)- 4-Chlorobenzoyl Difluorobenzylamine2-chloroacetamide chloride 3 D 3,5- N1-(3-Chlorophenyl)- 4-ChlorobenzoylDifluorobenzylamine 2-chloroacetamide chloride 4 D 2,3-N1-(3-Chlorophenyl)- 4-Chlorobenzoyl Difluorobenzylamine2-chloroacetamide chloride 5 D 2,4- N1-(3-Chlorophenyl)- 4-ChlorobenzoylDifluorobenzylamine 2-chloroacetamide chloride 6 D 2,5-N1-(3-Chlorophenyl)- 4-Chlorobenzoyl Difluorobenzylamine2-chloroacetamide chloride 7 D 4-Fluorobenzylamine N1-(3-Chlorophenyl)-4-Chlorobenzoyl 2-chloroacetamide chloride 8 D 3-FluorobenzylamineN1-(3-Chlorophenyl)- 4-Chlorobenzoyl 2-chloroacetamide chloride 9 D2-Fluorobenzylamine N1-(3-Chlorophenyl)- 4-Chlorobenzoyl2-chloroacetamide chloride 10 D Thiophen-3-yl- N1-(3-Chlorophenyl)-4-Methoxybenzoyl methylamine 2-chloroacetamide chloride 11 D 2,6-N1-(3-Chlorophenyl)- 4-Methoxybenzoyl Difluorobenzylamine2-chloroacetamide chloride 12 D 3,5- N1-(3-Chlorophenyl)-4-Methoxybenzoyl Dichlorobenzylamine 2-chloroacetamide chloride 13 D2,6- N1-(3-Chlorophenyl)- 4-Methoxybenzoyl Dichlorobenzylamine2-chloroacetamide chloride 14 D 3-Chlorobenzylamine N1-(3-Chlorophenyl)-4-Methoxybenzoyl 2-chloroacetamide chloride 15 D BenzylamineN1-(3-Chlorophenyl)- 4-Fluorobenzoyl chloride 2-chloroacetamide 16 Dbenzylamine N1-(3-Chlorophenyl)- 4-Chlorobenzoyl 2-chloroacetamidechloride 17 D Thiophen-2-yl- N1-(3-Chlorophenyl)- 4-Chlorobenzoylmethylamine 2-chloroacetamide chloride 18 D Thiophen-2-yl-N1-(3-Chlorophenyl)- 4-Methoxybenzoyl methylamine 2-chloroacetamidechloride 19 C (2,6-Dichloro- 3-Chloro aniline 4-Methoxybenzoylbenzylamino)-acetic chloride acid ethyl ester 20 D 3-Fluoroaniline2-Bromo-N-(3,4- 4-Methoxybenzoyl dichloro-phenyl)- chloride acetamide 21D 2-Fluoroaniline 2-Bromo-N-(3,4- 4-Methoxybenzoyl dichloro-phenyl)-chloride acetamide 22 B Aniline 2-Bromo-N-(3,4- 4-Methoxybenzoyldichloro-phenyl)- chloride acetamide 23 C Phenylamino-acetic 3-Chloro-2-4-Methoxybenzoyl acid ethyl ester Fluoroaniline chloride 24 CPhenylamino-acetic 5-Amino-2,2-difluoro- 4-Methoxybenzoyl acid ethylester 1,3-benzodioxole chloride 25 C Phenylamino-acetic 3-4-Methoxybenzoyl acid ethyl ester (Trifluoromethoxy)aniline chloride 26C Phenylamino-acetic m-Toluidine 4-Methoxybenzoyl acid ethyl esterchloride 27 C Phenylamino-acetic 3- 4-Methoxybenzoyl acid ethyl esterAminobenzotrifluoride chloride 28 C Phenylamino-acetic 3-Chloroaniline4-Methoxybenzoyl acid ethyl ester chloride 29 C Phenylamino-acetic3-methoxybenzonitrile 4-Methoxybenzoyl acid ethyl ester chloride 30 BAniline 2-Bromo-N-(3,4- 3-trifluoromethylbenzoyl dichloro-phenyl)-chloride acetamide 31 B Aniline 2-Bromo-N-(3,4- 3-cyanobenzoyl chloridedichloro-phenyl)- acetamide 32 B Aniline 2-Bromo-N-(3,4-2-Methoxybenzoyl dichloro-phenyl)- chloride acetamide 33 B Aniline2-Bromo-N-(3,4- 3-Methylbenzoyl dichloro-phenyl)- chloride acetamide 34A Aniline 2-Bromo-N-(4-methyl- 6-trifluoromethyl- phenyl)-acetamidenicotynoyl chloride 35 B Aniline 2-Bromo-N-(3,4- 3-Chlorobenzoyldichloro-phenyl)- chloride acetamide 36 A Aniline 2-Bromo-N-(4-fluoro-6-trifluoromethyl- phenyl)-acetamide nicotynoyl chloride 37 B Aniline2-Bromo-N-(3,4- 6-Trifluoromethyl- dichloro-phenyl)- nicotinoyl chlorideacetamide 38 B Aniline 2-Bromo-N-(3,4- 4-cyanobenzoyl chloridedichloro-phenyl)- acetamide 39 B Aniline 2-Bromo-N-(3,4- 2-Fluorobenzoylchloride dichloro-phenyl)- acetamide 40 B Aniline 2-Bromo-N-(3,4-3-fluorobenzoyl chloride dichloro-phenyl)- acetamide 41 B Aniline2-Bromo-N-(3,4- 4-methoxybenzoyl dichloro-phenyl)- chloride acetamide 42B Aniline 2-Bromo-N-(3,4- 4-fluorobenzoyl chloride dichloro-phenyl)-acetamide 43 D 2-Chloro-benzylamine 2-Chloro-N-(3- 3-Methylbenzoyltrifluoromethyl- chloride phenyl)-acetamide 44 D 2-Chloro-benzylamine2-Chloro-N-(3- 6-trifluoromethyl- trifluoromethyl- nicotynoyl chloridephenyl)-acetamide 45 D 3,5-difluoro- 2-Chloro-N-(3- 3-Chlorobenzoylbenzylamine trifluoromethyl- chloride phenyl)-acetamide 46 D3,5-difluoro- 2-Chloro-N-(3- 6-trifluoromethyl- benzylaminetrifluoromethyl- nicotynoyl chloride phenyl)-acetamide 47 D3,5-difluoro- 2-Chloro-N-(3- 6-Trifluoromethyl- benzylaminetrifluoromethyl- nicotinoyl chloride phenyl)-acetamide 48 D3,5-difluoro- 2-Chloro-N-(3- 4-cyanobenzoyl chloride benzylaminetrifluoromethyl- phenyl)-acetamide 49 D 3,5-difluoro- 2-Chloro-N-(3-2-Fluorobenzoyl chloride benzylamine trifluoromethyl- phenyl)-acetamide50 D 3,5-difluoro- 2-Chloro-N-(3- 4-cyanobenzoyl chloride benzylaminetrifluoromethyl- phenyl)-acetamide 51 D 2-Chloro-benzylamine2-Chloro-N-(3- Benzo[b]thiophene-2- trifluoromethyl- carbonyl chloridephenyl)-acetamide 52 D 2-Chloro-benzylamine 2-Chloro-N-(3-3-fluorobenzoyl chloride trifluoromethyl- phenyl)-acetamide 53 D2-Chloro-benzylamine 2-Chloro-N-(3- 4-Chlorobenzoyl trifluoromethyl-chloride phenyl)-acetamide 54 D 2-Chloro-benzylamine 2-Chloro-N-(3- 4-trifluoromethyl- trifluoromethoxybenzoyl phenyl)-acetamide chloride 55 D2-Chloro-benzylamine 2-Chloro-N-(3- 4-Fluorobenzoyl chloridetrifluoromethyl- phenyl)-acetamide 56 D 3,5-difluoro- 2-Chloro-N-(3-6-trifluoromethyl benzyl benzylamine trifluoromethyl- chloridephenyl)-acetamide 57 D 2-Chloro-benzylamine 2-Chloro-N-(3-fluoro-Benzo[b]thiophene-2- phenyl)-acetamide carbonyl chloride 58 D2-Chloro-benzylamine 2-Chloro-N-(3-fluoro- 3-fluorobenzoyl chloridephenyl)-acetamide 59 D 2-Chloro-benzylamine 2-Chloro-N-(3-fluoro-3-Methylbenzoyl phenyl)-acetamide chloride 60 D 2-Chloro-benzylamine2-Chloro-N-(3-fluoro- 4- phenyl)-acetamide trifluoromethoxybenzoylchloride 61 D 2-Chloro-benzylamine 2-Chloro-N-(3-fluoro- 4-Fluorobenzoylchloride phenyl)-acetamide 62 D 2-Chloro-benzylamine2-Chloro-N-(3-fluoro- 4-cyanobenzoyl chloride phenyl)-acetamide 63 D3,5-difluoro- 2-Chloro-N-(3-fluoro- Benzo[b]thiophene-2- benzylaminephenyl)-acetamide carbonyl chloride 64 D 3,5-difluoro-2-Chloro-N-(3-fluoro- 3-Methylbenzoyl benzylamine phenyl)-acetamidechloride 65 D 3,5-difluoro- 2-Chloro-N-(3-fluoro- 4- benzylaminephenyl)-acetamide trifluoromethoxybenzoyl chloride 66 D 3,4-difluoro-2-Chloro-N-(3-fluoro- Benzo[b]thiophene-2- benzylamine phenyl)-acetamidecarbonyl chloride 67 D 3,4-difluoro- 2-Chloro-N-(3-fluoro-3-Methylbenzoyl benzylamine phenyl)-acetamide chloride 68 D3,4-difluoro- 2-Chloro-N-(3-fluoro- 4- benzylamine phenyl)-acetamidetrifluoromethoxybenzoyl chloride 69 D 2,6-difluoro- 2-Chloro-N-(3-Benzo[b]thiophene-2- benzylamine Chloro,4-fluoro- carbonyl chloridephenyl)-acetamide 70 D 2,6-difluoro- 2-Chloro-N-(3- 3-Methylbenzoylbenzylamine Chloro,4-fluoro- chloride phenyl)-acetamide 71 D2,6-difluoro- 2-Chloro-N-(3- 4- benzylamine Chloro,4-fluoro-trifluoromethoxybenzoyl phenyl)-acetamide chloride 72 D2-Chloro-benzylamine 2-Chloro-N-(3- Benzo[b]thiophene-2-Chloro,4-fluoro- carbonyl chloride phenyl)-acetamide 73 D2-Chloro-benzylamine 2-Chloro-N-(3- 3-fluorobenzoyl chlorideChloro,4-fluoro- phenyl)-acetamide 74 D 2-Chloro-benzylamine2-Chloro-N-(3- 4-Chlrorobenzoyl Chloro,4-fluoro- chloridephenyl)-acetamide 75 D 2-Chloro-benzylamine 2-Chloro-N-(3- 4-Chloro,4-fluoro- trifluoromethoxybenzoyl phenyl)-acetamide chloride 76 D2-Chloro-benzylamine 2-Chloro-N-(3- 4-Fluorobenzoyl chlorideChloro,4-fluoro- phenyl)-acetamide 77 D 2-Chloro-benzylamine2-Chloro-N-(3- 4-cyanobenzoyl chloride Chloro,4-fluoro-phenyl)-acetamide 78 D 2,6-difluoro- 2-Chloro-N-(3- 4-Fluorobenzoylchloride benzylamine Chloro,4-fluoro- phenyl)-acetamide 79 D2-Chloro-benzylamine 2-Chloro-N-(3- 6-trifluoromethyl benzylChloro,4-fluoro- chloride phenyl)-acetamide 80 D 2,3-Difluoro-2-Chloro-N-(3- Benzo[b]thiophene-2- benzylamine Chloro,4-fluoro-carbonyl chloride phenyl)-acetamide 81 D 2,3-Difluoro- 2-Chloro-N-(3-3-fluorobenzoyl chloride benzylamine Chloro,4-fluoro- phenyl)-acetamide82 D 2,3-Difluoro- 2-Chloro-N-(3- 4-Chlrorobenzoyl benzylamineChloro,4-fluoro- chloride phenyl)-acetamide 83 D 2,3-Difluoro-2-Chloro-N-(3- 4- benzylamine Chloro,4-fluoro- trifluoromethoxybenzoylphenyl)-acetamide chloride 84 D 2,3-Difluoro- 2-Chloro-N-(3-4-Fluorobenzoyl chloride benzylamine Chloro,4-fluoro- phenyl)-acetamide85 D 2,3-Difluoro- 2-Chloro-N-(3- 4-cyanobenzoyl chloride benzylamineChloro,4-fluoro- phenyl)-acetamide 86 D 2,3-Difluoro- 2-Chloro-N-(3-6-trifluoromethyl benzyl benzylamine Chloro,4-fluoro- chloridephenyl)-acetamide 87 D 2,3-Difluoro- 2-Chloro-N-(3- Benzo[b]thiophene-2-benzylamine Chloro,4-fluoro- carbonyl chloride phenyl)-acetamide 88 D2,6-difluoro- 2-Chloro-N-(3- 4-cyanobenzoyl chloride benzylamineChloro,4-fluoro- phenyl)-acetamide 89 D 2,3-Difluoro- 2-Chloro-N-(3-3-Methylbenzoyl benzylamine Chloro,4-fluoro- chloride phenyl)-acetamide90 D 3,5-difluoro- 2-Chloro-N-(3- 4- benzylamine Chloro,4-fluoro-trifluoromethoxybenzoyl phenyl)-acetamide chloride 91 D 3,5-difluoro-2-Chloro-N-(3- 4-Fluorobenzoyl chloride benzylamine Chloro,4-fluoro-phenyl)-acetamide 92 D 3,5-difluoro- 2-Chloro-N-(3- 4-cyanobenzoylchloride benzylamine Chloro,4-fluoro- phenyl)-acetamide 93 D3,5-difluoro- 2-Chloro-N-(3- 6-trifluoromethyl benzyl benzylamineChloro,4-fluoro- chloride phenyl)-acetamide 94 D 3,4-Difluoro-2-Chloro-N-(3- Benzo[b]thiophene-2- benzylamine Chloro,4-fluoro-carbonyl chloride phenyl)-acetamide 95 D 2,2-simethyl2-Chloro-N-(3-Chloro 4-Chlrorobenzoyl propylamine phenyl)-acetamidechloride 96 D 3,3-dimethyl 2-Chloro-N-(3-Chloro 4-Chlrorobenzoylbutylamine phenyl)-acetamide chloride 97 E iso butylamine2-Bromo-N-(3,4- 4-Methoxybenzoyl dichloro phenyl)- chloride acetamide 98E 3-methyl butylamine 2-Bromo-N-(3,4- 4-Methoxybenzoyl dichloro phenyl)-chloride acetamide 99 B benzylamine 2-Bromo-N-(3,4- 4-Methoxybenzoyldichloro phenyl)- chloride acetamide 100 D 3-cyano-benzylamine2-Chloro-N-(3-chloro- 4-Chlorobenzoyl phenyl)-acetamide chloride 101 D3-methoxy- 2-Chloro-N-(3-chloro- 4-Chlorobenzoyl benzylaminephenyl)-acetamide chloride 102 D 2-methoxy- 2-Chloro-N-(3-chloro-4-Chlorobenzoyl benzylamine phenyl)-acetamide chloride 103 D3-methyl-benzylamine 2-Chloro-N-(3-chloro- 4-Chlorobenzoylphenyl)-acetamide chloride 104 D 2-methyl-benzylamine2-Chloro-N-(3-chloro- 4-Chlorobenzoyl phenyl)-acetamide chloride 105 D3-Chloro-benzylamine 2-Chloro-N-(3-chloro- 4-Chlorobenzoylphenyl)-acetamide chloride 106 D 2-Chloro-benzylamine2-Chloro-N-(3-chloro- 4-Chlorobenzoyl phenyl)-acetamide chloride 107 DC-Furan-2-yl- 2-Chloro-N-(3-chloro- 4-Chlorobenzoyl methylaminephenyl)-acetamide chloride 108 C Phenylamino-acetic 2-Bromo-N-(3,4-4-methoxy benzoyl acid ethyl ester dichloro phenyl)- chloride acetamide119 B 2-fluoro-benzylamine 3-Chloro aniline 6-Morpholin-4-yl- nicotinoylchloride 120 B 2-fluoro-benzylamine 3-Chloro aniline 6-Chloro-nicotinoylchloride 121 B 2-Fluoro-benzylamine 3-Chloro aniline2-Chloro-isonicotinoyl chloride 122 B 2-Fluoro-benzylamine 3-Chloroaniline 2,6-Dichloro- isonicotinoyl chloride 123 A C-Cyclohexyl-2-Chloro-N-(3-chloro- 4-chlorobenzoyl chloride methylaminephenyl)-acetamide 124 A C-Cyclohexyl- 2-Chloro-N-(3-chloro-4-Chlorobenzoyl methylamine phenyl)-acetamide chloride 125 AC-Cyclohexyl- 2-Chloro-N-(3-chloro- 4-Fluorobenzoyl chloride methylaminephenyl)-acetamide 126 A Cyclopentylamine 2,4-Dichloro-N-(3-4-Methoxybenzoyl chloro-phenyl)- chloride acetamide 127 ACyclopropylamine 2,4-Dichloro-N-(3- 4-Methoxybenzoyl chloro-phenyl)-chloride acetamide 128 A Cyclohexylamine 2,4-Dichloro-N-(3-4-Methoxybenzoyl chloro-phenyl)- chloride acetamide

The following compounds have been prepared in accordance with table 1:

TABLE 2 I

Procedure R¹ R² R³ R⁴ X IC₅₀ Exp D

H

bond 0.052 1 D

H

bond 0.265 2 D

H

bond 0.184 3 D

H

bond 0.074 4 D

H

bond 0.16 5 D

H

bond 0.165 6 D

H

bond 7 D

H

bond 0.128 8 D

H

bond 0.074 9 D

H

bond 0.285 10 D

H

bond 0.1 11 D

H

bond 0.243 12 D

H

bond 0.122 13 D

H

bond 0.024 14 D

H

bond 0.312 15 D

H

bond 0.156 16 D

H

bond 0.077 17 D

H

bond 0.257 18 C

H

bond 0.164 19 D

H

bond 20 D

H

bond 0.315 21 B

H

bond 22 C

H

bond 23 C

H

bond 24 C

H

bond 25 C

H

bond 26 C

H

bond 0.148 27 C

H

bond 0.267 28 C

H

bond 29 B

H

bond 30 B

H

bond 0.35 31 B

H

bond 32 B

H

bond 33 A

H

bond 34 B

H

bond 35 A

H

bond 36 B

H

bond 0.154 37 B

H

bond 38 B

H

bond 0.291 39 B

H

bond 40 B

H

bond 0.276 41 B

H

bond 42 D

H

bond 0.339 43 D

H

bond 44 D

H

bond 0.298 45 D

H

bond 46 D

H

bond 47 D

H

bond 48 D

H

bond 49 D

H

bond 50 D

H

bond 0.06 51 D

H

bond 0.153 52 D

H

bond 0.241 53 D

H

bond 0.196 54 D

H

bond 0.097 55 D

H

bond 56 D

H

bond 0.088 57 D

H

bond 58 D

H

bond 0.166 59 D

H

bond 0.107 60 D

H

bond 61 D

H

bond 0.357 62 D

H

bond 0.07  63 D

H

bond 64 D

H

bond 0.278 65 D

H

bond 0.167 66 D

H

bond 67 D

H

bond 68 D

H

bond 0.09 69 D

H

bond 70 D

H

bond 0.107 71 D

H

bond 0.205 72 D

H

bond 73 D

H

bond 0.142 74 D

H

bond 0.259 75 D

H

bond 0.159 76 D

H

bond 0.182 77 D

H

bond 0.282 78 D

H

bond 79 D

H

bond 0.066 80 D

H

bond 81 D

H

bond 0.108 82 D

H

bond 0.078 83 D

H

bond 0.178 84 D

H

bond 0.123 85 D

H

bond 86 D

H

bond 0.036 87 D

H

bond 0.199 88 D

H

bond 0.306 89 D

H

bond 0.288 90 D

H

bond 91 D

H

bond 92 D

H

bond 93 D

H

bond 94 D

H

bond 95 D

H

bond 0.359 96 E

H

bond 97 E

H

bond 98 B

H

bond 99 D

H

bond 0.192 100 D

H

bond 101 D

H

bond 0.06 102 D

H

bond 0.142 103 D

H

bond 0.209 104 D

H

bond 0.021 105 D

H

bond 0.025 106 D

H

bond 0.199 107 C

H

bond 0.182 108 C

H

bond 109 C

H

bond 0.369 110 C

H

bond 111 C

H

bond 112 B

H

bond 0.15 113 B

H

bond 0.091 114 B

H

bond 115 B

H

bond 0.191 116 B

H

bond 0.21 117 B

H

OCH₂ 0.259 118 B

H

bond 0.355 119 B

H

bond 0.182 120 B

H

bond 121 B

H

bond 122 A

CH₃

bond 123 A

H

bond 124 A

H

bond 125 A

H

bond 0.357 126 A

H

bond 127 A

H

bond 128

TABLE 3 MS MS Compound name MW result mode Example4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 449.28 447.0 neg 1N-(2,6-difluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 449.28 447.0 neg 2N-(3,4-difluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 449.28 447.0 neg 3N-(3,5-difluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 449.28 449.2 pos 4N-(2,3-difluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 449.28 449.2 pos 5N-(2,4-difluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 449.28 449.2 pos 6N-(2,5-difluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 431.29 431.4 pos 7N-(4-fluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 431.29 431.4 pos 8N-(3-fluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 431.29 431.4 pos 9N-(2-fluoro-benzyl)-benzamide N-[(3-Chloro-phenylcarbamoyl)-methyl]-4-414.9 415.3 pos 10 methoxy-N-thiophen-3-ylmethyl-benzamideN-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6- 444.9 443.2 neg 11difluoro-benzyl)-4-methoxy-benzamideN-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(3,5- 477.8 477.1 pos 12dichloro-benzyl)-4-methoxy-benzamideN-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,5- 477.8 479.2 pos 13dichloro-benzyl)-4-methoxy-benzamide N-(3-Chloro-benzyl)-N-[(3-chloro-443.3 443.3 pos 14 phenylcarbamoyl)-methyl]-4-methoxy-benzamideN-Benzyl-N-[(3-chloro-phenylcarbamoyl)-methyl]- 496.8 497.1 pos 154-fluoro-benzamide N-Benzyl-4-chloro-N-[(3-chloro-phenylcarbamoyl)-413.3 413.2 pos 16 methyl]-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 419.3 419.1 pos 17N-thiophen-2-ylmethyl-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 449.4 449.1 pos 18methoxy-N-thiophen-2-ylmethyl-benzamideN-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6- 477.8 479.2 pos 19dichloro-benzyl)-4-methoxy-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-(3- 447.3 447.1 pos 20fluoro-phenyl)-4-methoxy-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-(2- 447.3 447.1 pos 21fluoro-phenyl)-4-methoxy-benzamide Pentanoic acid[(3,4-dichloro-phenylcarbamoyl)- 379.3 379.3 pos 22 methyl]-phenyl-amideN-[(3-Chloro-2-fluoro-phenylcarbamoyl)-methyl]- 412.8 413.4 pos 234-methoxy-N-phenyl-benzamideN-[(2,2-Difluoro-benzo[1,3]dioxol-5-ylcarbamoyl)- 440.4 441.0 pos 24methyl]-4-methoxy-N-phenyl-benzamide4-Methoxy-N-phenyl-N-[(3-trifluoromethoxy- 444.4 445.1 pos 25phenylcarbamoyl)-methyl]-benzamide4-Methoxy-N-phenyl-N-(m-tolylcarbamoyl- 374.4 375.1 pos 26methyl)-benzamide 4-Methoxy-N-phenyl-N-[(3-trifluoromethyl- 428.4 429.0pos 27 phenylcarbamoyl)-methyl]-benzamideN-[(3-Chloro-phenylcarbamoyl)-methyl]-4- 394.9 395.0 pos 28methoxy-N-phenyl-benzamide 4-Methoxy-N-[(3-methoxy-phenylcarbamoyl)-390.4 391.3 pos 29 methyl]-N-phenyl-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N- 467.3 467.0 pos 30phenyl-3-trifluoromethyl-benzamide3-Cyano-N-[(3,4-dichloro-phenylcarbamoyl)- 424.3 467.0 pos 31methyl]-N-phenyl-benzamide N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-2-429.3 429.2 pos 32 methoxy-N-phenyl-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-3- 413.3 413.2 pos 33methyl-N-phenyl-benzamide N-Phenyl-N-(p-tolylcarbamoyl-methyl)-6- 413.4414.4 pos 34 trifluoromethyl-nicotinamide3-Chloro-N-[(3,4-dichloro-phenylcarbamoyl)- 433.7 433.0 pos 35methyl]-N-phenyl-benzamideN-[(4-Fluoro-phenylcarbamoyl)-methyl]-N-phenyl- 417.4 418.0 pos 366-trifluoromethyl-nicotinamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N- 468.3 468.1 pos 37phenyl-6-trifluoromethyl-nicotinamide4-Cyano-N-[(3,4-dichloro-phenylcarbamoyl)- 424.3 424.0 pos 38methyl]-N-phenyl-benzamide N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-2-417.3 417.3 pos 39 fluoro-N-phenyl-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-3- 417.3 417.1 pos 40fluoro-N-phenyl-benzamide N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4-429.3 429.3 pos 41 methoxy-N-phenyl-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 417.3 417.1 pos 42fluoro-N-phenyl-benzamide N-(2-Chloro-benzyl)-4-cyano-N-[(3- 471.9 472.2pos 43 trifluoromethyl-phenylcarbamoyl)-methyl]- benzamideN-(2-Chloro-benzyl)-3-trifluoromethyl-N-[(3- 514.9 515.2 pos 44trifluoromethyl-phenylcarbamoyl)-methyl]- benzamideBenzo[b]thiophene-2-carboxylic acid (3,5-difluoro- 504.5 506.2 pos 45benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)- methyl]-amideN-(3,5-Difluoro-benzyl)-3-fluoro-N-[(3- 466.4 467.2 pos 46trifluoromethyl-phenylcarbamoyl)-methyl]- benzamide4-Chloro-N-(3,5-difluoro-benzyl)-N-[(3- 482.8 483.4 pos 47trifluoromethyl-phenylcarbamoyl)-methyl]- benzamideN-(3,5-Difluoro-benzyl)-4-trifluoromethoxy-N-[(3- 432.4 433.2 pos 48trifluoromethyl-phenylcarbamoyl)-methyl]- benzamideN-(3,5-Difluoro-benzyl)-4-fluoro-N-[(3- 466.4 467.2 pos 49trifluoromethyl-phenylcarbamoyl)-methyl]- benzamide4-Cyano-N-(3,5-difluoro-benzyl)-N-[(3- 473.4 474.2 pos 50trifluoromethyl-phenylcarbamoyl)-methyl]- benzamideBenzo[b]thiophene-2-carboxylic acid (2-chloro- 502.9 503.1 pos 51benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)- methyl]-amideN-(2-Chloro-benzyl)-3-fluoro-N-[(3- 464.9 465.3 pos 52trifluoromethyl-phenylcarbamoyl)-methyl]- benzamide4-Chloro-N-(2-chloro-benzyl)-N-[(3- 481.3 481.2 pos 53trifluoromethyl-phenylcarbamoyl)-methyl]- benzamide#N!-(2-Chloro-benzyl)-4-trifluoromethoxy-#N!-[(3- 530.9 531.1 pos 54trifluoromethyl-phenylcarbamoyl)-methyl]- benzamideN-(2-Chloro-benzyl)-4-fluoro-N-[(3- 464.9 465.3 pos 55trifluoromethyl-phenylcarbamoyl)-methyl]- benzamideN-(3,5-Difluoro-benzyl)-3-trifluoromethyl-N-[(3- 516.4 517.2 pos 56trifluoromethyl-phenylcarbamoyl)-methyl]- benzamideBenzo[b]thiophene-2-carboxylic acid (2-chloro- 452.9 453.0 pos 57benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amideN-(2-Chloro-benzyl)-3-fluoro-N-[(3-fluoro- 414.8 415.3 pos 58phenylcarbamoyl)-methyl]-benzamide4-Chloro-N-(2-chloro-benzyl)-N-[(3-fluoro- 431.3 431.1 pos 59phenylcarbamoyl)-methyl]-benzamide N-(2-Chloro-benzyl)-N-[(3-fluoro-480.8 481.1 pos 60 phenylcarbamoyl)-methyl]-4-trifluoromethoxy-benzamide N-(2-Chloro-benzyl)-4-fluoro-N-[(3-fluoro- 414.8 415.2 pos 61phenylcarbamoyl)-methyl]-benzamideN-(2-Chloro-benzyl)-4-cyano-N-[(3-fluoro- 421.9 422.1 pos 62phenylcarbamoyl)-methyl]-benzamide Benzo[b]thiophene-2-carboxylic acid(3,5-difluoro- 454.5 455.2 pos 63benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide4-Chloro-N-(3,5-difluoro-benzyl)-N-[(3-fluoro- 432.8 433.2 pos 64phenylcarbamoyl)-methyl]-benzamide N-(3,5-Difluoro-benzyl)-N-[(3-fluoro-482.4 483.1 pos 65 phenylcarbamoyl)-methyl]-4-trifluoromethoxy-benzamide Benzo[b]thiophene-2-carboxylic acid (3,4-difluoro- 454.5 455.2pos 66 benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide4-Chloro-N-(3,4-difluoro-benzyl)-N-[(3-fluoro- 432.8 433.2 pos 67phenylcarbamoyl)-methyl]-benzamide N-(3,4-Difluoro-benzyl)-N-[(3-fluoro-482.4 483.4 pos 68 phenylcarbamoyl)-methyl]-4-trifluoromethoxy-benzamide Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4- 488.9 489.1pos 69 fluoro-phenylcarbamoyl)-methyl]-(2,6-difluoro- benzyl)-amide4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)- 467.3 467.1 pos 70methyl]-N-(2,6-difluoro-benzyl)-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 518.8 517.1 pos 71N-(2,6-difluoro-benzyl)-4-trifluoromethoxy- benzamideBenzo[b]thiophene-2-carboxylic acid (2-chloro- 487.4 487.2 pos 72benzyl)-[(3-chloro-4-fluoro-phenylcarbamoyl)- methyl]-amideN!-(2-Chloro-benzyl)-N!-[(3-chloro-4-fluoro- 449.3 449.1 pos 73phenylcarbamoyl)-methyl]-3-fluoro-benzamide4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro-4- 465.7 465.2 pos 74fluoro-phenylcarbamoyl)-methyl]-benzamideN-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro- 515.3 512.3 pos 75phenylcarbamoyl)-methyl]-4-trifluoromethoxy- benzamideN-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro- 449.3 449.1 pos 76phenylcarbamoyl)-methyl]-4-fluoro-benzamideN-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro- 456.3 456.3 pos 77phenylcarbamoyl)-methyl]-4-cyano-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 450.8 451.1 pos 78N-(2,6-difluoro-benzyl)-4-fluoro-benzamideN-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro- 499.3 499.2 pos 79phenylcarbamoyl)-methyl]-3-trifluoromethyl- benzamideBenzo[b]thiophene-2-carboxylic acid [(3-chloro-4- 488.9 489.2 pos 80fluoro-phenylcarbamoyl)-methyl]-(2,3-difluoro- benzyl)-amideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 450.8 451.1 pos 81N-(2,3-difluoro-benzyl)-3-fluoro-benzamide4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)- 467.3 467.2 pos 82methyl]-N-(2,3-difluoro-benzyl)-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 516.8 517.1 pos 83N-(2,3-difluoro-benzyl)-4-trifluoromethoxy- benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 450.8 451.1 pos 84N-(2,3-difluoro-benzyl)-4-fluoro-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 457.8 458.3 pos 854-cyano-N-(2,3-difluoro-benzyl)-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 500.8 501.1 pos 86N-(2,3-difluoro-benzyl)-3-trifluoromethyl- benzamideBenzo[b]thiophene-2-carboxylic acid [(3-chloro-4- 488.9 499.1 pos 87fluoro-phenylcarbamoyl)-methyl]-(3,5-difluoro- benzyl)-amideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 457.8 458.3 pos 884-cyano-N-(2,6-difluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)- 467.3 467.4 pos 89methyl]-N-(3,5-difluoro-benzyl)-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 516.8 517.1 pos 90N-(3,5-difluoro-benzyl)-4-trifluoromethoxy- benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 450.8 451.1 pos 91N-(3,5-difluoro-benzyl)-4-fluoro-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 457.8 458.3 pos 924-cyano-N-(3,5-difluoro-benzyl)-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 500.8 501.1 pos 93N-(3,5-difluoro-benzyl)-3-trifluoromethyl- benzamideBenzo[b]thiophene-2-carboxylic acid [(3-chloro-4- 488.9 489.1 pos 94fluoro-phenylcarbamoyl)-methyl]-(3,4-difluoro- benzyl)-amide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 393.3 393.1 neg 95N-(2,2-dimethyl-propyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 407.3 408.3 neg 96N-(3,3-dimethyl-butyl)-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N- 409.3 409.2 neg 97isobutyl-4-methoxy-benzamideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 423.3 421.0 neg 98methoxy-N-(3-methyl-butyl)-benzamideN-Benzyl-N-[(3,4-dichloro-phenylcarbamoyl)- 443.3 441.2 neg 99methyl]-4-methoxy-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 438.3 436.0 neg 100N-(3-cyano-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 443.3 440.9 neg 101N-(3-methoxy-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 443.3 440.9 neg 102N-(2-methoxy-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 427.3 446.8 neg 103N-(3-methyl-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 427.3 424.9 neg 104N-(2-methyl-benzyl)-benzamide 4-Chloro-N-(3-chloro-benzyl)-N-[(3-chloro-447.8 446.8 neg 105 phenylcarbamoyl)-methyl]-benzamide4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro- 447.8 446.8 neg 106phenylcarbamoyl)-methyl]-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 403.3 401.0 neg 107N-furan-2-ylmethyl-benzamideN-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 412.9 413.0 pos 1084-methoxy-N-phenyl-benzamideN-[(5-Chloro-2-methyl-phenylcarbamoyl)-methyl]- 408.9 409.2 pos 1094-methoxy-N-phenyl-benzamideN-[(3-Chloro-4-methyl-phenylcarbamoyl)-methyl]- 408.9 409.2 pos 1104-methoxy-N-phenyl-benzamideN-[(3,5-Dichloro-phenylcarbamoyl)-methyl]-4- 429.3 429.3 pos 111methoxy-N-phenyl-benzamideN-[(4-Bromo-3-chloro-phenylcarbamoyl)-methyl]- 473.8 472.9 pos 1124-methoxy-N-phenyl-benzamide Benzo[b]thiophene-2-carboxylic acid[(3,4-dichloro- 455.4 454.9 pos 113phenylcarbamoyl)-methyl]-phenyl-amideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N- 483.3 482.9 pos 114phenyl-4-trifluoromethoxy-benzamide Isoxazole-5-carboxylic acid[(3,4-dichloro- 390.2 390.0 pos 115phenylcarbamoyl)-methyl]-phenyl-amideN-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 442.3 442.0 pos 116dimethylamino-N-phenyl-benzamide N-(3-Chloro-phenyl)-N-[(3,4-dichloro-463.7 462.8 pos 117 phenylcarbamoyl)-methyl]-4-methoxy-benzamide2-(4-Chloro-phenoxy)-N-[(3,4-dichloro- 463.7 462.8 pos 118phenylcarbamoyl)-methyl]-N-phenyl-acetamideN-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2- 462.9 483.5 pos 119fluoro-benzyl)-6-morpholin-4-yl-nicotinamide6-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 432.3 432.2 pos 120N-(2-fluoro-benzyl)-nicotinamide2-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 432.3 432.1 pos 121N-(2-fluoro-benzyl)-isonicotinamide2,6-Dichloro-N-[(3-chloro-phenylcarbamoyl)- 466.7 468.1 pos 122methyl]-N-(2-fluoro-benzyl)-isonicotinamide4-Chloro-N-{[(3-chloro-phenyl)-methyl- 445.3 445.4 pos 123carbamoyl]-methyl}-N-(3-fluoro-benzyl)-benzamide4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 419.4 419.1 pos 124N-cyclohexylmethyl-benzamide N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-402.9 403.3 pos 125 cyclohexylmethyl-4-fluoro-benzamideN-Cyclopentyl-N-[(3,4-dichloro-phenylcarbamoyl)- 421.3 420.9 pos 126methyl]-4-methoxy-benzamideN-Cyclopropyl-N-[(3,4-dichloro-phenylcarbamoyl)- 393.3 393.0 pos 127methyl]-4-methoxy-benzamideN-Cyclohexyl-N-[(3,4-dichloro-phenylcarbamoyl)- 435.3 435.1 pos 128methyl]-4-methoxy-benzamide

1. A compound of formula I

wherein R¹ is heteroaryl, which is optionally substituted by halogen,lower alkyl, lower alkoxy, lower alkyl substituted by halogen, loweralkoxy substituted by halogen, cyano, amino, di-lower alkyl amino ormorpholinyl; R² is —(CH₂)_(n)-aryl, or —(CH₂)_(n)-heteroaryl wherein thearyl or heteroaryl groups are substituted by one or more substituentsselected from the group consisting of halogen, lower alkyl, cyano, andlower alkoxy; R³ is hydrogen or lower alkyl; R⁴ is aryl or heteroaryl,wherein aryl and heteroaryl are optionally substituted by one or moresubstituents selected from the group consisting of halogen, lower alkylsubstituted by halogen, lower alkoxy substituted by halogen, and loweralkyl; X is a bond or —OCH₂—; and n is 0, 1 or 2; or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A compound of claim 1, whereinX is a bond.
 3. A compound of claim 1, wherein R⁴ is monosubstitutedaryl.
 4. A compound of claim 3, wherein the monosubstituted aryl ishalogen substituted phenyl.
 5. A compound of claim 1, wherein R¹ isheteroaryl.
 6. A compound of claim 5, wherein R¹ is benzothiophenyl. 7.A compound of claim 6, selected from the group consisting ofBenzo[b]thiophene-2-carboxylic acid(2-chloro-benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-amide,Benzo[b]thiophene-2-carboxylic acid(2-chloro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,Benzo[b]thiophene-2-carboxylic acid(3,5-difluoro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,Benzo[b]thiophene-2-carboxylic acid[(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,6-difluoro-benzyl)-amide,Benzo[b]thiophene-2-carboxylic acid[(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,3-difluoro-benzyl)-amideand Benzo[b]thiophene-2-carboxylic acid[(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(3,5-difluoro-benzyl)-amide.8. A pharmaceutical composition comprising a compound of formula I

wherein R¹ is heteroaryl, which is optionally substituted by halogen,lower alkyl, lower alkoxy, lower alkyl substituted by halogen, loweralkoxy substituted by halogen, cyano, amino, di-lower alkyl amino ormorpholinyl; R² is —(CH₂)_(n)-aryl, or —(CH₂)_(n)-heteroaryl wherein thearyl or heteroaryl groups are substituted by one or more substituentsselected from the group consisting of halogen, lower alkyl, cyano, andlower alkoxy, R³ is hydrogen or lower alkyl; R⁴ is aryl or heteroaryl,wherein aryl and heteroaryl are optionally substituted by one or moresubstituents selected from the group consisting of halogen, lower alkylsubstituted by halogen, lower alkoxy substituted by halogen, and loweralkyl; X is a bond or —OCH₂—; and n is 0, 1 or 2; or a pharmaceuticallyacceptable acid addition salt thereof and a pharmaceutically acceptablecarrier.